The role of the cannabinoid system in fear memory and extinction in male and female mice
The role of the cannabinoid system in fear memory and extinction in male and female mice
复制标题
大麻素系统在雄性和雌性小鼠恐惧记忆和消退中的作用
DOI：
10.1016/j.psyneuen.2022.105688
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发表时间：
2022
影响因子：
3.7
通讯作者：
Mizutani A
中科院分区：
文献类型：
--
作者：
Mizuno I;Matsuda S;Tohyama S;Mizutani A
妇女的创伤后应激障碍发病率高于男子。在人类和小鼠中，雌性比雄性表现出更高的恐惧消退抵抗力，这表明恐惧消退过程中的性别差异与此类恐惧相关疾病的病理生理学有关。恐惧记忆和灭绝的分子机制的性别差异尚不清楚。众所周知，大麻素（CB）系统与恐惧记忆和灭绝有关，但这种参与主要基于使用雄性啮齿动物的实验。目前尚不清楚CB系统在恐惧记忆和灭绝中的作用是否存在性别差异。为了探索这种可能性，我们研究了CB系统的药理学操作对雄性和雌性小鼠背景恐惧记忆的恢复和消退的影响。WIN 55，212-2，CB受体（CBR）激动剂，增强检索的恐惧记忆在两种性别，但SR 141716（CB 1 R拮抗剂）没有影响它在任何性别。通过JZL 184（2-AG水解酶单酰基甘油脂肪酶[MAGL]的抑制剂）增强2-花生四烯酸甘油（2-AG，两种主要内源性大麻素之一），通过激活雌性小鼠中的CB 1 R而不是CB 2 R来增强恐惧记忆的恢复。与此相反，通过URB 597，一种AEA水解酶（脂肪酸酰胺水解酶-1）的抑制剂，N-花生四烯酸乙醇胺（AEA，其他主要的内源性大麻素）的增强没有表现出任何影响，在任何性别的恐惧记忆的检索。WIN 55、212-2、SR 141716和JZL 184抑制恐惧消退，与性别无关。URB增强了在第一次灭绝会议期间处于动情间期阶段的女性的恐惧灭绝，但在男性中没有。这些结果表明，虽然CB 1 R在检索和灭绝的上下文恐惧记忆中的作用是常见的男性和女性之间，内源性大麻素水平的增加对检索或灭绝的上下文恐惧记忆的影响在性别之间不同。
The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in fear-extinction processes are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms underlying fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It is not known whether there are sex differences in the role of the CB system in fear memory and extinction. To explore this possibility, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212–2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 (an inhibitor of the 2-AG hydrolase monoacylglycerol lipase [MAGL]), augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval of fear memory in either sex. WIN55,212–2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. URB enhanced fear extinction in females that were in diestrus phase at the first extinction session, but not in males. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in endocannabinoid levels on the retrieval or extinction of contextual fear memory differ between the sexes.